The most widely prescribed drugs to treat dermatologic disease are corticosteroids, also known as glucocorticosteroids or glucocorticoids. Approximately 50% of prescriptions written by dermatologists are for topical corticosteroids. Since the introduction of these substances in the early 1950s for dermatologic diseases, topical corticosteroid therapy continues to be the mainstay for the management of a broad spectrum of inflammatory dermatoses. Although systemic corticosteroids are often required in some severe dermatologic diseases, topical treatment is preferred in most responsive cases because it causes fewer systemic adverse effects.
Topical corticosteroids are generally effective in the treatment of acute and chronic dermatoses such as seborrheic dermatitis, atopic dermatitis, contact dermatitis of the irritant and allergic type, localized neurodermatitis (lichen simplex chronicus), lichen planus, and psoriasis. Steroids are also used for a variety of other less common conditions, such as Darier's disease and ichthyosiform dermatitis. A good overview of topical corticosteroid therapy appears in a series of papers presented at the Symposium on Topical Corticosteroids Today and Tomorrow, sponsored by Schering AG in Bali, Jun. 16-20, 1988, which were published in Drugs 36, Supplement 5, pp. 1-61 (Adis Press Ltd. 1988).
Individual topical corticosteroid preparations vary in anti-inflammatory potency and clinical efficacy. Therapeutic efficacy of steroid therapy can often be enhanced by increasing the potency of the steroid or by using special enhancers, such as occlusive dressings. In general, efficacy is dependent on multiple factors, viz. vehicle, site and frequency of application, disease, the individual patient, use of occlusive dressings, etc.
Potency of the corticosteroid preparation varies according to the particular corticosteroid selected, its concentration, and its vehicle. For convenience, topical corticosteroids, are classified into seven groups from most (Group I) to least (Group VII) potent as shown, for example, in Table I below. Further, these classifications are ranked according to relative potency designations with Group I usually designated as ultra high potency, Groups II and II designated as high potency, Groups IV and V designated mid potency, and Groups VI and VII designated low potency. Representative commercial corticosteroid preparations are set forth and classified according to this system in R. B. Stoughton, "Percutaneous Absorption of Drugs," Annual Review of Pharmacologic Toxicology, pp. 55-69 (1989).
TABLE I __________________________________________________________________________ POTENCY RANKING OF TOPICAL CORTICOSTEROIDS (Group I, most potent to Group VII, least potent) Group Usual Potency Generic Name Dosage Form Concentration __________________________________________________________________________ I. Betamethasone dipropionate cream, ointment 0.05% Clobetasol propionate cream, ointment 0.05% Diflorasone diacetate ointment 0.05% II. Amcinonide cream, ointment 0.1% Betamethasone dipropionate ointment 0.05% Diflorasone diacetate ointment 0.05% Halcinonide cream, ointment 0.1% Fluocinonide cream, ointment, solution, gel 0.05% Desoximetasone cream, gel, ointment 0.05%-0.25% Triamcinolone acetonide cream, ointment 0.5% Mometasone ointment 0.1% Fluocinolene acetonide cream 0.2% III. Triamcinolone acetonide ointment 0.1% Betamethasone dipropionate cream 0.05% Diflorasone diacetate cream 0.05% Betamethasone valerate ointment 0.1% Mometasone cream 0.1% IV. Flurandrenolide ointment 0.05% Triamcinolone acetonide cream, lotion 0.1% Fluocinolone acetonide ointment 0.025% Desoximetasone cream 0.05% Clocortolone pivalate cream 0.1% V. Flurandrenolide cream 0.05% Betamethasone dipropionate 0.05% Triamcinolone acetonide lotion 0.1% Hydrocortisone butyrate cream, ointment 0.1% Fluocinolone acetonide cream 0.025% Betamethasone valerate cream 0.1% Hydrocortisone valerate cream 0.2% VI. Desonide cream, ointment 0.05% Fluocinolone acetonide solution 0.01 Betamethasone valerate lotion 0.05% Aciometasone dipropionate cream, ointment 0.05% VII. Topicals with hydrocortisone, dexamethasone, flumethalone, prenisolon e, and methyprednisolone __________________________________________________________________________
Though some steroids, particularly mid- to high-potency steroids, are efficacious in chronic dermatoses, long term use of steroids is associated with serious local side effects. These include skin atrophy (thinning, telangiectasia, striae) and a prompt rebound flare when the steroid is stopped. Treatment of large areas of skin and use of occlusive dressings can also increase the potential for adverse effects. This is especially the case in children. As discussed more fully below, U.S. Pat. Nos. 4,889,847 and 5,019,569 disclose the use of retinoids, such as tretinoin, to prevent and reverse skin atrophy induced by corticosteroid therapy.
Topical retinoids such as tretinoin (all-trans-retinoic acid or Vitamin A acid) have been used by dermatologists for almost twenty years. For example, tretinoin is used topically in the treatment of acne vulgaris, primarily grades I-III, in which comedones, papules, and pustules predominate. See, for example, U.S. Pat. No. 3,729,568 of Kligman.
Tretinoin has been used effectively in the treatment of other skin conditions such a psoriasis, congenital ichthyosiform erythroderma, Darier's disease, epidermolytic hyperkeratosis, actinic keratosis, trichostasis, flat warts, basal cell carcinomas, and a variety of unrelated disorders. See, for example, J. R. Thomas et al. "The Therapeutic Uses of Topical Vitamin A Acid," Journal of the American Academy of Dermatology, 4:505-513 (1981).
More recently, it has been found that retinoids, such as tretinoin, particularly when used in separate, sequential topical applications with the corticosteroid, prevent and reverse skin atrophy in patients on long term corticosteroids for various skin diseases. See, for example, U.S. Pat. Nos. 4,889,847 and 5,019,569 of Kligman, Mezick and Capetola, the disclosures of which are incorporated herein by reference. However, that work was concerned with preventing and reversing the side effects of corticosteroid therapy and did not address the possibility of enhanced efficacy, especially for those patients whose disease has become resistant to corticosteroids. Dermatologists call this acquired resistance "tachyphylaxis" and try to mitigate it by various strategies, such as rest periods (interval therapy) and switching to another drug. These approaches are only marginally helpful.